The molecular mechanism of P23H rhodopsin autosomal dominant retinitis pigmentosa (adRP) is still not clear, and currently there is no effective treatment for this retinal degenerative disease. Certain findings suggest that misfolded P23H opsin is the main trigger of photoreceptor death whereas others indicate that the mutant rhodopsin instead disrupts the disc organization of rod outer segments to cause this effect. The short term goal of this proposed study is to determine the predominant molecular mechanism of P23H rhodopsin- related photoreceptor death, and identify novel therapeutics that prevents this retinopathy. Aim 1 of this study focuses on the discovery and characterization of pharmacological chaperones of P23H opsin, and use developed lead compounds to test whether stabilizing P23H opsin prevents photoreceptor death in P23H mouse model. Experiments for Aim 1 will be undertaken in the candidate's dependent phase. Aim 2 is to identify and characterize pharmacological enhancers of P23H opsin clearance, which will be tested for their effects in prevention of photoreceptor degeneration and correction of disc organization in outer segments. The proposed experiments for Aim 2 will be accomplished in the candidate's independent phase. Novel small-molecule compounds have been identified by two high-throughput screens, which either rescue the translocation of P23H opsin or enhance its clearance in cell culture. Molecular pathways perturbed by these compounds initially will be identified by in vitro studies. The efficacy and potency of such compounds will be validated and improved in cell culture systems. Qualified compounds then will be further evaluated in a transgenic C. elegans model for their effects on neuron protection and biochemical properties of P23H rhodopsin. Finally, one or two lead compounds from each drug discovery strategy will be tested in P23H/+ knock-in mice to evaluate their protective effects on retinal structure and function, including the maintenance of disc organization in rod outer segments. Results from these experiments will suggest the dominant mechanism for photoreceptor death, and more importantly, candidates for treatment of P23H adRP. Under mentorship of Dr. Krzysztof Palczewski, the candidate will strengthen and extend her training in drug discovery and development for retinal diseases. Through close collaboration with Drs. Phoebe Stewart, Akiko Maeda, and Marcin Golczak, the candidate will have access to a combination of cutting edge techniques including medicinal chemistry, ultra-high resolution imaging of retinal structures, functional analysis of retina, and cryo-electron tomography. The candidate's progress in science and career development will be under supervision of an advisory committee to aid in her transition from a postdoctoral trainee to an independent investigator. In the long term, the candidate is interested in mechanistic and drug discovery studies of other blinding retinal diseases.